Neoplastic disease is characterized by inappropriate cell proliferation relative to the rate of differentiation. A variety of agents which can induce transformed cells to express characteristics of a differentiated state and cease proliferating have been identified for use in the treatment of human cancers. Such agents include relatively simple polar/apolar compounds, retinoic acid and its derivatives, vitamin D.sub.3 and its derivatives, tumor promoters, inhibitors of RNA or DNA synthesis including several agents used as cytotoxic therapy for cancers, growth factors, such as hematopoietic-cell growth factors, proteases, and hormones. The basic defect in cancers involves an imbalance in the relationship between proliferation of precursor cells and the differentiation of these cells. Differentiation factors can normalize the relationship of proliferation to differentiation. Consideration of a use for differentiating factors in the treatment of human cancers is based largely upon in vitro studies that have demonstrated the effectiveness of these agents in inducing a wide variety of transformed cell lines to differentiate and stop growing. The successful treatment of human acute promyelocytic leukemia by retinoic acid established that cytodifferentiation therapy may have utility in the treatment of human malignancies. The clinical evaluation of additional differentiating agents has begun more recently.
Butyric acid has been shown to induce cytodifferentiation in vitro in a wide variety of neoplastic cells. Chen, Z. and Brutman, T. R. Cancer Res. 1994, 54:3494-3499. The potential utility of this agent as an antineoplastic has been limited, however, by the apparent difficulty in achieving effective concentrations of butyric acid in vivo. Chen and Brutman studied the effect of the prodrugs monobutyrin and tributyrin in vitro in inducing differentiation of human myeloid leukemia HL60 cells and murine erythroleukemia cells. Butyric acid, monobutyrin and tributyrin all induced erythroid differentiation of erythroleukemia. However, on a molar basis tributyrin was 3- to 4-fold more potent than butyric acid, whereas monobutyrin was much less potent than butyric acid. Based upon these experiments, it was suggested that tributyrin may be a promising candidate as a prodrug of butyric acid, either as a sole agent or in combination with other agents, for cytodifferentiation therapy of human leukemia and other malignancies and possibly for patients with .beta.-hemoglobinopathies. Chen, Z. and Brutman, T. R. Cancer Res. 1994, 54:3494-3499.
Another differentiating agent, sodium phenylacetate, has been evaluated as an alternative to cytotoxic chemotherapy in the treatment of cancer. Phenylacetate has been demonstrated to promote maturation of various human leukemic cell lines. In addition, its use has been suggested in the treatment of prostate cancer. Samid et al. J. Clin. Invest. 1993, 91:2288-2295. Phenylacetate has been demonstrated to suppress tumor growth and promote differentiation in experimental models. Thibault et al. Can. Res. 1994, 54:1690-1694. It has also been shown that sodium phenylacetate and its precursor, sodium 4-phenylbutyrate, enhance fetal hemoglobin production in cultured erythroid progenitor derived from normal donors and patients with sickle cell anemia and .beta.-thalassemia.
There is also increasing evidence to suggest that 1,25-dihydroxy vitamin D.sub.3 (1,25-(OH).sub.2 D.sub.3), or calcitrol, has important physiological effects on growth and differentiation in a variety of malignant and nonmalignant cell types. One of the earliest demonstrations of the antiproliferative effects of 1,25-(OH).sub.2 D.sub.3 was with the HL-60 human promyelocytic leukemia cell line. Treatment with physiological doses of 1,25(OH).sub.2 D.sub.3 suppressed cell growth and induced monocytic differentiation. Similar growth-inhibiting and differentiation-inducing effects have been demonstrated in vitro in other cell types including normal human bone cells, and in malignant cell lines derived from breast, malignant melanoma, histiocytic lymphoma and colon carcinoma. Halline et al. Endocrinology 1994, 134(4):1710-1717.
Differentiating agents such as 1,25(OH).sub.2 D.sub.3 and analogs thereof, have also been used in the treatment of diseases related to disordered epidermal differentiation. In addition to producing vitamin D, epidermal cells (keratinocytes) make 1,25(OH).sub.2 D.sub.3, contain 1,25(OH).sub.2 D.sub.3, and respond to 1,25(OH).sub.2 D.sub.3 with changes in proliferation and differentiation. Bikle, D. D. and Pillai, S. Endocrine Reviews 1993, 14(1):3-19. 1,25(OH).sub.2 D.sub.3 has been found to inhibit IL-1.alpha. induced IL-8 production and mRNA expression in keratinocytes, fibroblasts and PBMC, but not in endothelial cells. Larsen et al. Biochem. Biophys. Res. Commun. 1991, 176(3) 1020-1026. Calcipotriol is a vitamin D.sub.3 analog which also inhibits cell proliferation and enhances cell differentiation. Calcipotriol has pharmacodynamic properties similar to those of calcitriol, the active metabolite of vitamin D.sub.3. In several in vitro models both calcipotriol and calcitriol inhibit cell proliferation and enhance cell differentiation. Both drugs reduce cell numbers, total DNA content and incorporation of radiolabeled thymidine into DNA and increase the number of human keratinocytes with cornified envelopes and activity of enzyme-caused, protein crosslinking in the envelopes. In patients with psoriasis, calcipotriol also reduces dermal proliferation and enhances differentiation in lesional skin. Murdoch, D. and Clissold, S. P. Drugs 1992, 43(3):415-429.
It has now been found that differentiating agents are also useful in the treatment of intestinal inflammatory diseases. Differentiating agents which alter the state of proliferation and ultimately the differentiation of colonic epithelial cells reduce the inflammation associated with intestinal diseases such as ulcerative colitis.